The present invention relates firstly to 3-azabicyclo[3.1.0]hexanes with an amino function carrying two protective groups in position 6. The present invention further relates to processes for the preparation of these compounds starting from chloroenamines or bicyclic nitriles, and the modification by cleaving off the protective groups in a customary manner. Finally, the present invention relates to the use of the novel aminioazabicyclohexanes for the preparation of quinolone- and naphthyridinecarboxylic acid derivatives such as 7-(6-amino-3-azabicyclo[3.1. 0]hexyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naph-thyrid ine-3-carboxylic acid and salts thereof, and optionally to subsequent modification by cleaving off the protective groups.
It is known that 6-amino-3-azabicyclo[3.1.0]hexanes is used as diamine component for the preparation of gyrase inhibitors (cf. WO 91/02526, U.S. Pat. No. 5,164,402, EP-A 413 455, Synlett 1996, 1097. U.S. Pat. No. 5,298,629, WO 93/18001 and Synlett 1996, 1100). In the process, preference is given to using the more readily available 6-exo-amine.
In the syntheses of 6-exo- and 6-endo-amino-3-azabicyclo[3.1.0]hexane to date, the 6-amino group is always obtained alter the cyclopropanation step by converting a functional group. Here, compounds with monoprotected 6-amino groups are used in each case.
In the invention presented below, the amino group is already present in the molecule in the cyclopropanation step. However, the amino group is initially protected by two protective groups, such as, for example, benzyl or allyl radicals, which can be cleaved off later or following incorporation of the novel aminoazabicyclohexanes into quinolone- or naphthyridinecarboxylic acid derivatives. Despite an opposing opinion expressed in the literature (cf. Synlett 1996, 1100), this route is therefore a practical way of also obtaining 6-amino-3-azabicyclo[3.1.0]hexane derivatives having a free amino group in position 6. The starting materials chosen in the novel process are chloroenamines or else bicyclic nitriles preparable therefrom. Chloroenamines give exclusively the 6-endo-amino-3-azabicyclo[3.1.0]hexanes, whilst either 6-endo- or 6-exo-aminio-3-azabicyclo[3.1.0]hexanes are obtainable from the bicyclic nitriles.
The present invention relates to novel 6-amino-3-azabicyclo[3.1.0]hexanes of the formula ##STR2##
in which
R.sup.1 and R.sup.2 independently of one another are C.sub.3 -C.sub.4 -alkenyl or Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl and PA1 R.sup.3 is hydrogen, C.sub.3 -C.sub.4 -alkenyl, Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl or COOR.sup.4 where R.sup.4 =C.sub.1 -C.sub.4 -alkyl or C.sub.2 -C.sub.4 -alkenyl. PA1 R' is preferably hydrogen. PA1 R.sup.1 and R.sup.2 are identical and are C.sub.3 -C.sub.4 -alkenyl or Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl, and PA1 R.sup.3 has the same scope of meaning as R.sup.1 and R.sup.2, but can be different from R.sup.1 and R.sup.2, PA1 R.sup.1, R.sup.2 and R.sup.3 are as defined for formula (II), PA1 R.sup.1, R.sup.2 and R.sup.3 are as defined above for formula (II). PA1 R.sup.1 and R.sup.2 are identical and are Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl, and PA1 R.sup.3 has the same scope of meaning as R.sup.1 and R.sup.2, but can be different from R.sup.1 and R.sup.2, PA1 R.sup.1 and R.sup.2 are as defined for formula (I), and PA1 R.sup.5 is hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.4 -alkenyl, Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl or COOR.sup.4 where R.sup.4 =C.sub.1 -C.sub.4 -alkyl or C.sub.2 -C.sub.4 -alkenyl, PA1 R.sup.1 and R.sup.2 are as defined for formula (I), and PA1 R.sup.3 is hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.4 -alkenyl, Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.1 C.sub.10 -aryl or COOR.sup.4 where R.sup.4 =C.sub.1 -C.sub.4 -alkyl or C.sub.2 -C.sub.4 -alkenyl. PA1 R.sup.6 is hydrogen.
The optionally substituted C.sub.6 -C.sub.10 -aryl can, for example, be unsubstituted C.sub.6 -C.sub.10 -aryl or C.sub.6 -C.sub.10 -aryl substituted with from 1 to 3 identical or different substituents. Suitable substituents are, for example, C.sub.1 -C.sub.4 -alkyl and C.sub.1 -C.sub.4 -alkoxy.
In preferred compounds of the formula (I), R.sup.1 and R.sup.2 are identical and are allyl or benzyl and R.sup.3 is hydrogen, allyl, benzyl, COOCH.sub.3 or COOCH.dbd.CH.sub.2.
The discussed compounds of the formula (I) have two stereoisomers of the formulae ##STR3##
which, should a more accurate name be needed below, are referred to as endo-(I) and exo-(I) respectively. R.sup.1, R.sup.2 and R.sup.3 in the formulae endo-(I) and exo-(I) correspond to the radicals given for formula (I).
The present invention also relates to a process for the preparation of compounds of the formula endo-(I), which is characterized in that a chloroenamines of the formula ##STR4##
in which
is reacted with a C.sub.1 -C.sub.4 -alkyl alkoxide, to give an N,O-acetal of the formula (III), ##STR5##
in which
the latter is treated with a hydride conversion agent, giving an amine of the formula ##STR6##
in which
This process of the present invention is characterized by very high stereoselectivity. The cyclopropane formation from the chloroenamines of the formula (II) and subsequent substitution in the N,O-acetals of the formula (III), which have a tertiary acetalic amine unit, always lead to endo-amine derivatives of the formula endo-(I).
Chloroenamines of the formula (II) can be obtained in a known manner or analogously thereto, for example by reacting 1-[C.sub.3 -C.sub.4 -alkenyl or Ar--CH(R') where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl]-4-di-[C.sub.3 -C.sub.4 -alkenyl or Ar--CH(R')-- where R'=hydrogen or C.sub.1 -C.sub.4 -alkyl and Ar=optionally substituted C.sub.6 -C.sub.10 -aryl-]amino-1,2,5,6-tetrahydropyridine with N-chlorosuccinimide (see Tetrahedron 51, 3507 (1995)).
In the process, the substituted 4-aminotetrahydropyridine used may preferably be 1-benzyl-4-dibenzylamino-1,2,5,6-tetrahydropyridine and 1-benzyl-4-diallylamino-1,2,5,6-tetrahydropyridine. The reaction mixture produced in the chlorination can also be further used as such, i.e. without isolation of the chloroenamines of the formula (II).
The C.sub.1 -C.sub.4 -alkyl alkoxides are generally used together with a solvent, preferably in alcoholic solution, for example dissolved in an alcohol which corresponds to the respective alkoxide radical. Preference is given to the sodium methoxide/methanol system, which can be prepared very simply from elemental sodium and excess methanol. Preference is given to using a two- to fourfold molar excess of alkoxide with respect to the chloroenaminie. The reaction often proceeds at a sufficient rate at room temperature. It can be speeded up by heating to e.g. 50 to 60.degree. C.
When reaction with the C.sub.1 -C.sub.4 -alkyl alkoxide is complete, the resulting N,O-acetal of the formula (III) can be isolated and purified by, for example, firstly stripping off the solvent, extracting the residue which remains with a solvent, e.g. a hydrocarbon, and isolating the N,O-acetal of the formula (III) from the extract, e.g. by crystallization or distillation under reduced pressure.
Particularly when, during the reaction of a chloroenamines of the formula (II) with a C.sub.1 -C.sub.4 -alkyl alkoxide, the chloroenamines of the formula (II) is added as a powder to a solution of a C.sub.1 -C.sub.4 -alkyl alkoxide in a C.sub.1 -C.sub.4 -alkyl alcohol, the 6-endo-amine isomer of the N,O-acetal [as shown in formula (III)] is exclusively obtained.
Suitable hydride conversion agents for substituting the C.sub.1 -C.sub.4 -alkoxy group in the N,O-acetal of the formula (III) by hydrogen are, for example, hydrides, such as lithium aluminium hydride or diisobutyl aluminium hydride. Suitable solvents for this substitution reaction arc, for example, ethers, preference being given to tetrahydrofuran. N,O-acetals of the formula (III) and hydride conversion agents can be used, for example, in a molar ratio of from 1:1.2 to 1:4. The reaction is preferably carried out in a temperature range from, for example, 50 to 70.degree. C. It is generally completed within 3 to 5 hours.
The substitution reaction with the hydride conversion agent can be carried out, for example, by initially introducing the hydride conversion agent suspended in a suitable suspending agent, adding a solution of the N,O-acetal of the formula (III) dropwise, stripping off the suspending agent and solvent after the reaction is complete, hydrolyzing the residues, separating off the solid constituents from the mixture then present, extracting the aqueous phase which remains, and isolating the amine of the formula endo-(I) prepared from the extract.
The solvent used for the N,O-acetal of the formula (III) is preferably the suspending agent for the hydride conversion agent. Suitable for the alkaline hydrolysis is, for example, an aqueous alkali metal hydroxide solution, it being possible, if desired, to pour the reaction mixture into aqueous mineral acid beforehand. Extraction of the aqueous phase can be carried out, for example, using ethers, such as diethyl ether.
Suitable methods for isolating the amine of the formula endo-(I) are, for example, crystallization from a nonpolar solvent, such as pentane, or distillation at reduced pressure.
The present invention also relates to a process for the preparation of compounds of the formula endo-(I), which is characterized in that a chloroenamines of the formula ##STR7##
in which
is reacted directly with a hydride conversion agent, the resulting primary product is subjected to acidic hydrolysis, and the amine of the formula endo-(I) is liberated by lye. This process likewise proceeds with high stereoselectivity, with the formation of the endo-amine isomers of the formula endo-(I).
This reaction can be carried out, for example, in acetonitrile or an acetonitrile/water mixture (e.g. 9:1 to 2.5:1) with heating to, for example, from 40 to 70.degree. C. Suitable hydride agents are, for example, complex hydrides stable to water and acetonitrile. Sodium borotetrahydride is preferred. Chloroenamines and hydride conversion agents can be used, for example, in a molar ratio from 1:5 to 1:10. The amine adduct formed primarily in the process is cleaved by hydrolysis with acid, preferably hydrochloric acid. The amine of the formula endo-(I) is liberated by subsquently adding lye, e.g. by adding aqueous lye, such as dilute potassium hydroxide solution.
The present invention further relates to a process for the preparation of amines of the formula (I), which is characterized in that a bicyclic nitrile of the formula ##STR8##
in which
is reacted with an alkali metal in liquid ammonia, optionally in the mixture with a mono- or dialkylamine. The alkyl groups of these amines preferably contain from 1 to 4 carbon atoms. Preference is given to using ethylamine. This process can be used to stereoselectively prepare 6-amino-3-azabicyclo[3.1.0]hexane derivatives of the formula endo-(I) and exo-(I),
in which
Bicyclic nitriles of the formula (IV) are obtainable, for example, in accordance with Tetrahedron 51, 3507 (1995) from chloroenamines or analogously to the procedure described therein. According to the invention, the nitrile group in the nitrile of the formula (IV) can be replaced by hydrogen with an alkali metal in liquid ammonia or in a mixture of ammonia and a mono- or dialkylamine, preferably ethylamine.
For the reaction, the nitrile and the alkali metal can be reacted in a molar ratio of, for example, from 1:3 to 1:8. Preference is given to a ratio of from 1:5 to 1:7. Per mmol of nitrile of the formula (IV), it is possible to use, for example, from 15 to 100 ml, preferably from 15 to 25 ml, of ammonia or alkylamine/ammonia mixture. The temperature used plays an important role for the stereochemical progress of the reaction. Carrying out the reaction at from -70.degree. C. to -40.degree. C. effects substitution with complete or almost complete retention of the configuration on the C(6), with formation of the 6-endo-amine isomers of the formula endo-(I). If, on the other hand, the analogous reaction of a nitrile of the formula (IV) where R.sup.1 =R.sup.2 benzyl and R.sup.5 =hydrogen is carried out in a mixture of ethylamine and ammonia at .+-.0.degree. C. using sodium or, preferably, lithium as alkali metal, then a stereoisomer mixture of amines of the formula exo-(I) and endo-(I) where R.sup.1 =R.sup.2 =benzyl and R.sup.3 =hydrogen is obtained. The 6-exo-amine isomer of the formula exo-(I) mentioned is generally present in an amount of (80.+-.10)%; it can be obtained as pure compound by crystallization or other separation methods. It corresponds to a 3-azabicyclo[3.1.0]hexane with an amine group carrying two protective groups in position 6-exo; this is a derivative of the diamine building block in the gyrase inhibitor described in the introduction.
The present invention further includes the modification of the bicyclic compounds, obtained via chloroenamines of the formula (II) or from nitrites of the formula (IV), of the formula ##STR9##
where R.sup.1, R.sup.2 and R.sup.3 can be as defined for formulae (II) and (IV), by cleaving off the protective groups in formulae II and IV in a customary manner.
Suitable reactions for cleaving off the protective groups from an amine of the formula (I) are, for example, a hydrogenating treatment, reaction with chloroformic C.sub.2 -C.sub.4 -alkenyl esters and subsequent acidic hydrolysis, reaction with chloroformic C.sub.1 -C.sub.4 -alkyl ester to give an urethane and its cleavage with halogenotrialkylsilane or deallylation with tetrakis(triaryl)phosphinepalladium and a CH acid, such as N,N'-di-alkylbarbituric acid.
The hydrogenating treatment can be carried out, for example, with hydrogen in the presence of a noble metal catalyst. Suitable catalysts are, for example, elemental palladium, in particular elemental palladium on a support such as carbon, aluminium oxide, silicon dioxide or silicates. The hydrogenating treatment can likewise be carried out in a solvent. Suitable solvents for this purpose are, for example, alcohols such as methanol, to which tertiary amines, such as triethylamine, can optionally be added. The other reaction conditions for this hydrogenating treatment (e.g. pressure, temperature etc.) and for working-up the reaction mixture produced can be chosen in ways known for such reactions from the prior art. According to these methods, it is possible, for example in the amine of the formula endo-(I) where R.sup.1 =R.sup.2 =R.sup.3 =benzyl, to reductively remove all benzyl groups by hydrogen. This produces an amine of the formula ##STR10##
in which
Selective removal of the N(3)-CH(R')--Ar group in an amine of the formula (I) can, for example, take place by reacting with chloroformic aceto-C.sub.2 -C.sub.4 -alkenyl ester and subsequent acidic hydrolysis of the resulting urethane. Particularly suitable for this purpose are a benzyl group on N(3) in the amine and vinyl chloroformate. This conversion to the urethane is preferably carried out in a solvent. Examples are dichloromethane, chloroform and acetonitrile, chloroform being preferred. Vinyl chloroformate and amine can be used, for example, in the molar ratio of (1.1 to 1.2):1. Reaction temperatures in the range from 40 to 60.degree. C. and reaction times from 1 to 3 hours generally lead to good results. Separating off the coproduct benzyl chloride and purifying the urethane can be carried out by distillation under reduced pressure. Under the conditions described, dibenzylamine hydrochloride is formed as a by-product. Cleaving off the vinyloxycarbonyl group in the urethane, e.g. with concentrated hydrochloric acid in chloroform, and working up with lye gives the partially deprotected amine of the formula (I). In these methods, it is possible, for example, in an amine of the formula endo-(I) in which R.sup.1 =R.sup.2 =R.sup.3 =benzyl, to selectively replace the benzyl radical R.sup.3 by hydrogen.
Selective removal of the N(3)-CH(R')--Ar group in an amine of the formula (I) can also be carried out by reaction with chloroformic C.sub.1 -C.sub.4 -alkyl esters and subsequent reaction with a halogenotrialkylsilane. Particularly suitable for this purpose are a benzyl group on N(3) in the amine and methyl chloroformate, and cleavage of the resulting urethane with trimethylsilyl iodide. The reaction to give the urethane is preferably carried out in a solvent. Examples arc dichloromethane and chloroform in a mixture with pyridine. Chloroform/pyridine in a ratio of (4 to 6):1 is preferred. Methyl chloroformate and amine can be reacted, for example, in a molar ratio of (1.5 to 2):1. Reaction temperatures in the range from 40 to 60.degree. C. and reaction times from 3 to 6 hours generally lead to good results. Separating off the coproduct benzyl chloride and purifying the urethane can be carried out by distillation under reduced pressure. Under the described conditions, dibenzylamino hydrochloride is formed as by-product. Cleaving off the methoxycarbonyl group in the urethane with halogeno-trialkylsilane, in particular trimethylsilyl iodide, is preferably carried out in solvent, such as chloroform, at from 40 to 70.degree. C., preferably at from 50 to 65.degree. C. Halogeno-trialkylsilane can be used, for example, in a 4- to 6-fold molar excess. As a rule, the reaction is complete after 5 to 8 hours. It is then expedient to carry out acid hydrolysis. In this connection, good results are achieved using methanolic hydrogen chloride solution. Working up with lye then releases the amine of the formula (I). In these methods, it is possible, for example in an amine of the formula endo-(I) in which R.sup.1 =R.sup.2 =R.sup.3 =benzyl, to selectively replace the benzyl radical R.sup.3 by hydrogen. Alternatively, it is possible, for example, to also debenzylate the resulting urethane of the formula endo-(I) where R.sup.1 =R.sup.2 =benzyl and R.sup.3 =COOCH.sub.3 to give the amine of the formula (V) where R.sup.6 =COOCH.sub.3.
For the deallylation, the compound of the formula (I) where R.sup.1 and R.sup.2 =C.sub.3 -C.sub.4 -alkenyl is, for example, reacted with N,N'-dimethylbarbituric acid or a similar compound and tetrakis(triphenylphosphine)palladium or an analogous derivative, preferably in a molar ratio of 1:(3 to 4):(0.01 to 0.05). It is also possible to choose these molar ratios differently. Suitable solvents for this purpose are, for example, chlorinated hydrocarbons, such as methylene chloride. Thus, the diallyl compound of the formula endo-(I) where R.sup.1 =R.sup.2 =allyl and R.sup.3 =benzyl can, for example, be deallylated in the presence of, for example, tetrakis(triphenylphosphine)palladium using N,N'-dimethylbarbituric acid to give the monobenzyl compound of the formula (V) There R.sup.6 =benzyl. The reaction is preferably carried out in dichloromethane at, for example, from 30 to 40.degree. C. Preference is given to using the starting material N,N'-dituethylbarbituric acid and tetrakis(triphentylphosphine)palladium, in a ratio of 1:(3.0 to 3.5):(0.01 to 0.03).
In all reactions which proceed with removal of benzyl or allyl protective groups, the configuration on the C(6) of the 3-aza-bicyclo[3.1.0]hexane system is not changed.
The present invention also relates to the use of the novel compounds of the formula (I) for the preparation of quinolone- and naphthyridinecarboxylic acid derivatives with optional subsequent modification of the 6-amino radical by cleaving off the protective groups. Thus, for example, 7-(6-endo-amino-3-azabicyclo[3.1. 0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acid and salts thereof in particular are accessible. In this connection, it is possible, for example, to proceed in accordance with the following equation. ##STR11##
7-(6-Endo-amino-3-azabicyclo[3.1. 0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acid and its salts are characterized, in contrast to the corresponding 6-exo-amine isomers, by significantly lower neurotoxicity. According to an analogous equation, it is also possible to prepare, from the novel 6-exo-amine isomers of the formula exo-(I) where R.sup.1 =R.sup.2 =benzyl and R.sup.3 =H, 7-(6-exo-amino-3-azabicyclo[3.1. 0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acid and its salts.